The gp120 and gp41 envelope glycoproteins of human immunodeficiency virus (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), play important roles in virus entry into target cells and in viral cytopathic effect. Since the HIV-1 envelope glycoproteins are exposed on the virion, they represent critical targets for therapeutic intervention and vaccine development. Antibodies that neutralize virus infectivity in vitro and that, in some cases, have been shown to be protective in vivo are directed against both variable and conserved regions of the HIV-1 envelope glycoproteins. The relatively well- conserved discontinuous epitopes on the HIV-1 gp120 glycoprotein constitute attractive targets for immunological intervention. Two groups of such epitopes have been defined - those that overlap the CD4 binding site on the gp120 glycoprotein (CD4 binding site, CD4bs) and those whose exposure is increased by CD4 binding (CD4-induced, CD4i). The specific aims for this proposal are: 1. To determine the functional significance of the exposure of the CD4i epitopes to virus entry. 2. To identify mutant HIV-1 gp120 glycoproteins that exhibit a high spontaneous exposure of the CD4i or CD4bs epitopes and to test whether such mutants might be better immunogens than the wild-type gp120 glycoprotein for elicitation of more broadly reactive antibodies. 3. To study the HIV-1-neutralizing properties of mutant antibodies that recognize CD4i epitopes with high affinity.